Inhibitory effects of the essential divalent metals, magnesium and zinc, on the carcinogenicity and acute toxicity of a divalent metal carcinogen, nickel, have been investigated in carcinogenesis, toxicity, and biochemical studies. Magnesium has been found to counteract nickel carcinogenesis in rat muscle in a dose-dependent mode. It prolongs the latent period and substantially decreases the incidence of nickel-induced sarcomas, while zinc prolongs the latency of tumors without significant effect on their incidence. The inhibitory action of magnesium is strictly local; that of zinc is systemic. Magnesium greatly attenuates the post-injection necrosis and inflammation, particularly the immediate infiltration of neutrophils into the site of injection. Similarly in mice, i.p. injections of nickel cause a vivid infiltration of inflammatory cells that can be inhibited by a simultaneous injection of magnesium. Neither magnesium nor nickel, alone or combined, have any effect on natural killer cell activity in rat blood and injected muscle. Magnesium and zinc appear to be equally effective in antagonizing acute toxicity of nickel, but their individual mechanisms of action are different. Magnesium affects pharmacokinetics, while zinc affects the pharmacodynamics of nickel in rats. Likewise different are the two physiological metals in inhibiting nickel-DNA interactions in vitro. Further exploration of the mechanisms of nickel interactions with magnesium and zinc with more emphasis on the role of all three metals in the mediation of local inflammatory reactions is underway.